Pharmaceutical Development and

Review Process

Rev. 10/21/2014

APGO Interaction with Industry: A Medical Student Guide

ObjectivesLearn the processes involved in drug discovery and

development in the United States

Understand the role of the Food and Drug Administration (FDA) in the drug development and review process in the US

Define the phases involved in FDA drug approval

Overview-Research and Development Process (R&D)

Development of new drugs is a complex and costly process

It takes an average of 9 years and $850 million to take a “chemical entity” from the lab to the pharmacy shelf

R&D involves discovery, preclinical studies and development

One out of every 1,000 compounds that begin preclinical studies will ultimately be marketed

Brief Flow Diagram of the Drug Approval Process

Preclinical/animal studies

Investigational new drug (IND) application

Clinical studies (Phases 1-3)

New drug application

FDA/CDER review

Approval

Post approval evaluation/Phase 4

A History of Federal Oversight of the Drug Development Process

The Food and Drug Administration (FDA) is the Federal agency that is required by law to review and approve all new drugs in the US.

The 1906 Food and Drugs Act prohibited mislabeling but did not require pre-market approval of drugs.

The 1938 Food, Drugs and Cosmetics Act required submission of evidence of a drug’s safety before it could be marketed.

The Role of the FDAThe FDA reviews and evaluates new drugs based on

evidence presented from the clinical research studies performed by the drug sponsor-typically a pharmaceutical company

The Center for Drug Evaluation and Research (CDER) is the largest of the FDA’s five centers and is responsible for prescription and over-the-counter (OTC) drug safety and efficacy

Preclinical StudiesSynthesis and purification of the new drug

Pharmacology of the new drug:Pharmacokinetics: absorption, distribution,

metabolism, excretion, half-lifePharmacodynamics: mechanism of action and

estimates of therapeutic effectsToxicology including carcinogenicity, mutagenicity

and teratogenicity

Safety studies on animals

Definitions-Investigational New Drug (IND)

New drug applications (NDAs) require clinical trials using the candidate chemical compound for safety and efficacy, usually in centers in multiple states

Federal law requires that a drug be the subject of a marketing application before transporting across state lines

The IND is the process by which an exemption to the law is obtained

Studies in humans can only begin after IND is reviewed and approved by the FDA and an institutional review board (IRB)

Overview of Clinical Study PhasesPhase 1: Safety and tolerability studies on healthy

volunteers

Phase 2: Clinical studies to demonstrate proof of concept and dose findings

Phase 3: Efficacy and safety studies on large number of subjectsNDA regulatory review

Phase 4: Post-marketing safety studies

Phase 1 Clinical StudiesTypically 20-80 healthy volunteers

Emphasis on drug safety

Identify major side-effects, metabolism, routes of excretion

Duration: about 1 year

Sufficient information about pharmacokinetics and effects to permit design of well-controlled Phase 2 studies

About 70% that make it to this phase will pass

Phase 2 Clinical StudiesTypically involves 100-300 individuals who have the target

disease

Emphasis on effectiveness

Closely monitored, can evaluate short-term side-effects and risks

Patients receiving the drug are compared to similar patients receiving a placebo or another drug

Duration: about 2 years

About 33% of drugs will pass this phase

Phase 3 Clinical StudiesTypically involves 1,000-3,000 patients

Emphasis on safety and effectiveness

Investigates different populations and dosages as well as combination with other drugs

Extrapolation to a general population

Acquire data used for physician labeling

Duration: about 3 years

25-30% pass this phase

The Role of the Institutional Review Board (IRB)

IRBs ensure the rights and welfare of people participating in clinical trials, both before and during trial participation

IRBs make sure that participants are fully informed and have given written consent before participating in studies

IRBs are located in hospitals and research centers

Definition-New Drug Application (NDA)

Starting with the 1938 and subsequent (increasingly demanding) amendments, all the data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) are required to become part of the NDA

While varying by type of compound, an NDA can consist of as many as 15 different sections

NDA (cont’d)Pre-NDA period: FDA and drug sponsors meet

Submission of NDA: Formal step asking FDA to consider approving a drug for marketing

FDA has 1 year to decide whether it will file the NDA for approval consideration

If filed, a review team is assigned to evaluation the new drug

FDA ApprovalFDA review team evaluates the research on safety

and effectiveness

Labeling information reviewed

Inspection of production facilities

Decision and justification letter:Not approvableApprovableApproval

FDA Approval (cont’d)Not approvable: Lists deficiencies in application and

why it cannot be approved

Approvable: Ultimately can be approved and lists deficiencies that can be corrected, including labeling changes and requests for post-approval studies

Approval: Drug is approved

Phase 4 Clinical StudiesPost-market surveillance of the drug to continually

assess safety of the drug

May include incidence and severity of rare adverse reactions, cost-effectiveness analyses, comparative trials, and quality of life studies

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm Accessed 7/9/2014

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm Accessed 7/9/2014

Resourceshttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/

default.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm176522.htm